A Personalized Signature and Chronotherapy-Based Platform for Improving the Efficacy of Sepsis Treatment

Abstract

Sepsis remains a major therapeutic challenge and is associated with a high rate of morbidity and mortality. It is a dynamic condition in which multiple parameters change over time, rendering it difficult to overcome the various injurious responses, which worsen the prognosis in these patients. The prognosis of sepsis is associated with a disbalance of compensatory responses to infectious triggers, part of which can be deleterious. Marked inter-and intra-patient variability characterizes the mechanisms that underlie sepsis progression and determine the response to therapy. In this paper, we review some of the data on the use of chronopharmacological approaches for the treatment of patients with sepsis and discuss the role of the autonomic nervous system in the mechanisms associated with immune response and chronotherapy in these patients. We describe the implementation of an individualized platform that is based on the personalized autonomic nervous system, immune, and chronobiologyderived parameters for generating a patient-tailored therapeutic regimen. The notion of overcoming the deleterious compensatory response in a highly dynamic system in sepsis is presented to ensure an improved response to current therapies.

Order Through Disorder: The Characteristic Variability of Systems

“…Variability in biological systems can be viewed as a contributing modality of their function (Clarke and Crame, 2010;Farahpour et al, 2018). Randomness can be considered as a property of causal processes, contributing to complex system function (Ilan, 2019e;Kenig and Ilan, 2019;Khoury and Ilan, 2019). Random genetic drift is accepted as the random fluctuations in the numbers of gene variants in a population (Lynch et al, 2016).…”

“…The optimal state in variability may have a U shape between a chaotic pattern of variability in a steady state and full predictability in a normal biological system (Stergiou and Decker, 2011;Ilan, 2019a,b,c,e,f). Dosing of medications using regular fixed regimens may not be compatible with the physiological variability in the immune system and may further contribute to loss of response (Weiner et al, 1980;Toni and Tidor, 2013;Ilan, 2019c;Kenig and Ilan, 2019;Khoury and Ilan, 2019).…”

“…Under certain conditions, promoting or making use of variability-associated parameters, may be necessary for improving the function of processes and systems (Ilan, 2019f). It was also proposed to be use as a method for improving and/or correcting malfunction or disease states (El-Haj et al, 2019;Ilan, 2019d,f;Kenig and Ilan, 2019;Khoury and Ilan, 2019).…”

Targeting SARS-CoV-2 receptors as a means for reducing infectivity and improving antiviral and immune response: an algorithm-based method for overcoming resistance to antiviral agents

“…The unpredictability of drug effectiveness is partly associated with the dynamicity and continuously changing rules by which these systems function. Dosing regimens of drugs, which are based on regular fixed schedules, have been proposed to be incompatible with the physiological variability by which these systems operate, leading to primary or secondary loss of response [92,93].…”

“…A patient-tailored approach, which implements personalized variability patterns into treatment algorithms, has been proposed to improve the treatment sustainability. Patterns of variability can be quantified based on host and disease-related variability patterns, immune tests, genetic profiling, chronotherapy, heart rate variability, and additional parameters [92,93]. Algorithm-controlled treatment regimens are now being used in several clinical trials for overcoming drug resistance (NCT03843697; NCT03747705).…”